Cystoid macular edema (CME) is a common feature in retinitis pigmentosa (RP), affecting up to 1/3 of patients. RP-associated CME has been related to retinal neuroinflammation and microglial activation. Minocycline, a FDA-approved antibiotic, exerts off-label inhibition of microglial activation and decreases inflammatory factor production, and has been found to exert neuroprotection in RP animal models. The objective of this study is to investigate the safety and possible efficacy of oral minocycline as a primary treatment for CME in RP. A single-center, prospective, open-label Phase I/II clinical trial enrolled five participants with bilateral CME associated with RP. One eye in each participant was assigned as the study eye and the contralateral eye as the fellow eye. Participants were followed monthly for 3 months off-drug and then administered oral minocycline 100 mg twice daily for 12 months. Main outcome variables included:(1) changes in best corrected visual acuity (BCVA) and (2) changes in retinal central subfield thickness (CST) measured using spectral domain optical coherence tomography (SD-OCT) relative to mean pretreatment measurements. The study drug was well tolerated and not associated with any significant adverse events. No significant changes in mean BCVA were noted in either the study eye or the fellow eye (P>0.05 for all comparisons). Changes relative to baseline were <10 letters for all eyes. Mean percentage changes in CST however decreased progressively with time on treatment. Considering all eyes (n = 10), a decrease in CST decrease at 6 and 12 months (p=0.63) and (p=0.03) respectively. Minocycline administration over 12 months was associated with: A small but progressive and significant decrease in mean central macular thickness. No significant changes in mean visual acuity No significant change in average microperimetry responses. Further study is needed to determine whether minocycline is a potentially useful mode of intervention for macular edema in the setting of RP.